Efficacy of candidate topical microbicides in prevention of HIV-1 transmission.

Our laboratory focuses on the use of non-human primate (NHP) models to study HIV infection and the progressive development of AIDS. Experimental infections of rhesus macaques with CXCR4- and CCR5-tropic simian-human immunodeficiency viruses (SHIVs) are conducted to assess the impact of coreceptor usage in virus transmission and pathogenesis, as well as to identify the genotype and phenotype of the transmitted and pathogenic viruses. Most HIV-1 transmission results in a predominantly R5 virus infection. With time, X4 variants arise and coexist with R5 virus varainats in ~50% of subtype B infected individuals, and this event is associated with rapid CD4+ T cell loss and disease progression. We recently observed X4 virus evolution in a R5 SHIV infected macaque as disease progresses, demonstrating that coreceptor switch can happen in an animal model of HIV/AIDS. The identification of an R5 virus that can switch to CXCR4 usage in a relevant animal model of HIV/AIDS provides the experimental system critically needed to dissect the mechanistic basis for and obstacles to coreceptor switch in vivo. This system can also be employed to determine whether the use of CCR5 inhibitors will hasten the pace of X4 virus evolution.

NHP studies are also an important tool for delineating the correlates of protection, information of which will contribute to the design of improved AIDS vaccine candidates. For these reasons, we are actively engaged in characterizing the breath, depth and site of immune responses in macaques that control viremia to levels below the limit of detection, and in those that are continuously exposed and yet remain negative for serum antibodies and detectable virus. Lastly, given the current epidemic trend, there is an urgent need to expand the range of interventions such as the use of topical microbicides that can be controlled by women. Experiments are being conducted to assess the safety, distribution and efficacy of candidate topical microbicides in the SHIV/macaque model. For the latter purpose, a repeated low-dose mucosal exposure protocol that more likely mimics HIV-1 sexual transmission in humans has been established. Using this challenge protocol, synergism between suboptimal vaccines and topical microbicides in conferring protection against virus transmission will also be evaluated.

The main research efforts of the Cheng-Mayer laboratory are aimed at advancing our understanding of the mechanisms of HIV transmission and pathogenesis. Infection of non-human primates (NHP) with simian immunodeficiency viruses carrying the envelope glycoproteins of HIV-1 reproduces many features of HIV-1 infection in humans. Using this animal model, we sort to determine whether certain virus variants are more transmissible or are better at causing disease in the hosts. The ways in which the virus evolves from a less pathogenic towards more pathogenic variants, as well as the specific immune responses (antibodies, CD4+ or CD8+ T cell responses, or combination of these) that protect macaques from infection or disease development are also being studied. The latter will provide vital clues to the type of responses that would be required to protect against HIV infection in humans. Lastly, the increasing feminization of the AIDS pandemic brings into focus the need to expand the range of interventions, such as topical microbicides that can be controlled by women. We are actively engaged, using the macaque model, in identifying safe and efficacious microbicide products that could be advanced for clinical testing in humans.